Container for linezolid intravenous solution

ABSTRACT

The present invention is a container for an IV aqueous solution of a Gram-positive oxazolidinone agent, such as linezolid a the compound of formula:  
                 
which comprises having the container-solution contact surface material be a polyolefin.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of the following provisionalapplication: U.S. Ser. No. 60/191,383, filed Mar. 22, 2000, under USC119(e)(i).

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention is the use of polyolefins as the material in IV containerswhich is in contact with pharmaceutically useful antibacterialoxazolidinone agents during and after moist heat sterilization.

2. Description of the Related Art

Oxazolidinones are well known to those skilled in the art as grampositive anti-bacterial agents, see, for example, U.S. Pat. Nos.5,688,792, 5,529,998, 5,547,950, 5,627,181, 5,700,799, 5,843,967,5,792,765, 5,684,023, 5,861,413, 5,827,857, 5,869,659, 5,698,574,5,968,962 and 5,981,528.

Various containers are known to hold aqueous solutions to beadministered IV to a patient. The most common IV solution containers areglass and plastic bottles and plastic bags.

U.S. Pat. No. 4,803,102 discloses containers for IV solutions where thematerial in contact with the aqueous solution to be administered IV ismade primarily of polyolefin(s).

SUMMARY OF INVENTION

Disclosed is a container for an IV aqueous solution of a Gram-positiveoxazolidinone agent which comprises having the container-solutioncontact surface material is made of at least 50% polyolefin.

Also disclosed is a method of preventing loss of a Gram-positiveoxazolidinone agent during and following terminal sterilization withmoist heat in an IV aqueous solution to be terminal sterilized withmoist heat which comprises:

-   -   (1) placing the IV aqueous solution in a container to be        sterilized where the container-solution contact surface material        is made of at least 50% polyolefin and    -   (2) moist heat sterilizing the container-solution.

DETAILED DESCRIPTION OF THE INVENTION

Oxazolidinones are a new class of Gram-positive antibacterial agentswhich are known to those skilled in the art, see for example U.S. Pat.No. 5,688,792.(S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide,known as linezolid, the compound of Example 5 of U.S. Pat. No. 5,688,792is known and has the following chemical formula:

(S)-N-[[3-[3-fluoro-4-[4-(hydroxyacetyl)-1-piperazinyl]-phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide,known as eperezolid, the compound of Example 8 of U.S. Pat. No.5,837,870 is known and has the following chemical formula:

Linezolid and eperezolid can be produced by the processes set forth inU.S. Pat. Nos. 5,688,791 and 5,837,870 as well as that of InternationalPublication WO99/24393. It is preferably produced by the process of U.S.Pat. No. 5,837,870.

It is preferred that the linezolid produced be used in crystal form II,which has the characteristics set forth in CHART A. Once linezolid issynthesized, crystal Form II is prepared by starting with linezolid ofhigh enantiomeric purity. It is preferred that the linezolid be morethan 98% enantiomerically pure, it is more preferred that the linezolidbe more than 99% pure and it is even more preferred that the linezolidbe 99.5% pure. The linezolid of greater than 98% enantiomeric purity tobe used to form crystal form II can either be in solution or be a solid.The linezolid starting material, solid or solution, is mixed with asolvent selected from the group consisting of compounds of the formula:water, acetonitrile, chloroform, methylene chloride, R₁—OH where R₁ isC₁-C₆ alkyl; R₁—CO—R₂ where R₂ is C₁-C₆ alkyl and R₁ is as definedabove; phenyl substituted with 1 thru 3 R₁ where R₁ is as defined above;R₁—CO—O—R₂ where R₁ is C₁-C₆ alkyl and R₁ is as defined above; R₁—O—R₂where R₁ is C₁-C₆ alkyl and R₁ is as defined above. It is preferred thatthe solvent be selected from the group consisting of water, ethylacetate, methanol, ethanol, propanol, isopropanol, butanol,acetonitrile, acetone, methyl ethyl ketone, chloroform, methylenechloride, toluene, xylene, diethyl ether, or methyl-t-butyl ether. It ismore preferred that the solvent be ethyl acetate, acetone, acetonitrile,propanol, or isopropanol. It is most preferred that the solvent be ethylacetate. The mixture of linezolid in the solvent is agitated at atemperature below 800 until crystals of Form II are formed and crystalsof other solid forms, such as Form I, disappear. It is preferred todissolve the linezolid in ethyl acetate at a temperature near theboiling point of the solvent. This mixture is cooled to a temperature ofabout 70°. The mixture may be seeded with crystals of Form II tofacilitate crystallization. It is preferred that the solid product iscooled and agitated at a temperature between about 45° and about 60°until the solids consist only of Form II crystals. It is most preferredto maintain the slurry at a temperature of about 55°. It is preferred tomix the linezolid and solvent for at least 10 min, it is even morepreferred to mix the linezolid and solvent for at least 20 min and it ismost preferred to mix the linezolid and solvent for at least 30 min. Thetime and temperature will vary depending on the solvent selected. Withethyl acetate it is preferred to mix for not less that 60 minutes. Thecrystalline slurry may be further cooled to improve yield, and the solidForm II product may be isolated. The mixture may be further cooled andagitated. Other measures which can be used to facilitate crystallizationinclude, but are not limited to, cooling, concentration of the solutionby evaporation or distillation, or through addition of other solvents.The crystals are isolated by procedures known to those skilled in theart.

It is well known to those skilled in the art that the oxazolidinones areuseful as anti-bacterial agents especially against Gram-positiveorganisms. U.S. Pat. No. 5,688,792 discloses that oxazolidinones can beadministered IV. The preferred formulation for linezolid IV solution is:Linezolid  2.0 mg/mL Sodium Citrate Dihydrate (USP)  1.64 mg/mL CitricAcid Anhydrous (USP)  0.85 mg/mL Dextrose Monohydrate (USP) 50.24 mg/mLHydrochloric Acid (10%) q.s. to pH 4.8 (pH 4.6 to 5.0) Sodium hydroxide(10%) q.s. to pH 4.8 (pH 4.6 to 5.0) Water for Injection (USP) q.s. ad1.0 mLThe linezolid IV solution is formulated by heating water for injectionfrom about 50 to about 65°. Next the sodium citrate, citric acid anddextrose are added and stirred until dissolved. An aqueous slurry oflinezolid is added to the previous mixture and stirred until dissolved.The mixture is cooled to 25° with stirring. The pH is measured andadjusted if necessary. Last the mixture is brought to volume, ifnecessary, with water for injection. The mixture is filtered, filledinto infusion containers, over wrapped and terminally moist heatsterilized.

The aqueous solution for IV administration can be placed in thecontainer which is selected from the group consisting of a bag, abottle, a vial, a large volume parenteral, a small volume parenteral, aprefilled syringe and a cassette. It is realized that a vial is abottle. However, those skilled in the art use the term “bottle” torefers to larger bottles and “vials” to refer to smaller bottles. It ispreferred that the container be a bag, a bottle, a vial or a prefilledsyringe. It is more preferred that the container be a bag or bottle. Itis most preferred that the container be a bag. The shape and/or size ofthe container is unimportant. It is preferred that the container be abag sufficient to hold 25 to 2,000 mL of IV solution. It is preferredthat the linezolid mixture be put in bags in amounts of 100, 200 or 300mL of solution however smaller or larger volumes are acceptable.

It is well known to those skilled in the art that pharmaceutical agentsadministered IV must be sterile. While there are a number of methods tosterilize an IV solution, it is preferred to terminally moist heat orsteam sterilize IV solutions of oxazolidinones including those oflinezolid. When the term terminally “moist heat sterilize” is used, itrefers to and includes steam sterilization.

When terminally moist heat sterilizing an IV solution, the solution isplaced in the container in which (1) it will be stored and thentransferred to the container from which it will ultimately beadministered, or (2) stored and then ultimately administered from thesame container to deliver the IV solution to the patient. Therefore, itis imperative that the pharmaceutically active ingredient(oxazolidinone, linezolid) not react with the container in which it isto be terminally moist heat sterilized and stored/stored-administered.

It has been found that when the container-solution contact surface ismade of at least 50% polyolefin there is significantly much less loss oflinezolid during and following terminal moist heat sterilization. Whatis essential is that the container-solution contact surface material beprimarily a polyolefin; the remainder of the container can be made frompolyolefin or other materials. It is preferred that thecontainer-solution contact surface is made of from about 50 to about100% polyolefin. It is more preferred that the container-solutioncontact surface is made of from about 70 to about 90% polyolefin. It ismore preferred that the container-solution contact surface is made offrom about 80% polyolefin. It is even more preferred that thecontainer-solution contact surface is made of polyolefin.

Polyolefins include, for example, polyethylene, polypropylene,polybutenes, polyisoprenes and polypentenes and copolymers and mixturesthereof. It is preferred that the polyolefin be selected from the groupconsisting of polyethylene and polypropylene. It is more preferred thatthe polyolefin be polypropylene or mixture of polypropylene andpolyethylene.

Definitions and Conventions

The definitions and explanations below are for the terms as usedthroughout this entire document including both the specification and theclaims.

Definitions

Linezolid refers to(S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamideis the compound of formula:

Eperezolid refers to(S)-N-[[3-[3-fluoro-4-[4-(hydroxyacetyl)-1′-piperazinyl]-phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide is the compound of formula:

All temperatures are in degrees Celsius.

Polyolefins (as defined in Whittington's Dictionary of Plastics, JamesF. Carley, Ed., Technomic Publishing Co., Lancaster, Pa., 1993) refersto any of the largest genus of thermoplastics, polymers of simpleolefins such as ethylene, propylene, butenes, isoprenes, and pentenesand copolymers and modifications thereof.

IV refers to intravenous.

“Heat sterilize” and “moist heat sterilize” refers to and includes steamsterilization.

Pharmaceutically acceptable refers to those properties and/or substanceswhich are acceptable to the patient from a pharmacological/toxicologicalpoint of view and to the manufacturing pharmaceutical chemist from aphysical/chemical point of view regarding composition, formulation,stability, patient acceptance and bioavailability.

EXAMPLES

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, practice the present invention toits fullest extent. The following detailed examples describe how toprepare the various compounds and/or perform the various processes ofthe invention and are to be construed as merely illustrative, and notlimitations of the preceding disclosure in any way whatsoever. Thoseskilled in the art will promptly recognize appropriate variations fromthe procedures both as to reactants and as to reaction conditions andtechniques.

Example 1 Linezolid IV Solution (1 mL)

The composition of Linezolid IV solution is as follows: Linezolid 2.0 mgDextrose, USP 50.24 mg Sodium citrate, USP 1.64 mg Citric acid, USP 0.85mg Water for injection, USP q.s. ad 1 ml

The linezolid IV solution is formulated by heating water for injectionto 60°. Next the sodium citrate, citric acid and dextrose are added andstirred until dissolved. An aqueous slurry of linezolid is added to theprevious mixture and stirred until dissolved. The mixture is cooled to25° with stirring. The pH is measured and adjusted if necessary. Lastthe mixture is brought to volume, if necessary with water for injection.The mixture is filtered, filled into infusion containers, over wrappedand terminally moist heat sterilized.

Example 2 Linezolid IV Solution (300 mL)

Following the general procedure of EXAMPLE 1 and making non-criticalvariations but using 300 times the amount of each ingredient, 600 mg oflinezolid, the title IV solution is prepared. CHART A Linezolid,(S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide, crystal “Form II” has the powder X-raydiffraction spectrum of: Two-Theta Relative d-Spacing (Á) Angle (°)Intensity (%) 12.44 7.10 2 9.26 9.54 9 6.37 13.88 6 6.22 14.23 24 5.4816.18 3 5.28 16.79 100 5.01 17.69 2 4.57 19.41 4 4.50 19.69 2 4.45 19.936 4.11 21.61 15 3.97 22.39 23 3.89 22.84 4 3.78 23.52 7 3.68 24.16 13.52 25.28 13 3.34 26.66 1 3.30 27.01 3 3.21 27.77 1and an infrared (IR) spectrum (mineral oil mull) of 3364, 1748, 1675,1537, 1517, 1445, 1410, 1401, 1358, 1329, 1287, 1274, 1253, 1237, 1221,1145, 1130, 1123, 1116, 1078, 1066, 1049, 907, 852 and 758 cm⁻¹.

1. A container for an IV aqueous solution of a Gram-positiveoxazolidinone agent which comprises having the container-solutioncontact surface material is made of at least 50% polyolefin.
 2. Acontainer for an IV aqueous solution according to claim 1 where thecontainer is selected from the group consisting of a bag, a bottle, avial, a large volume parenteral, a small volume parenteral, a prefilledsyringe and a cassette.
 3. A container for an IV aqueous solutionaccording to claim 2 where the container is a bag, a bottle, a vial anda prefilled syringe.
 4. A container for an IV aqueous solution accordingto claim 2 where the container is a bag.
 5. A container for an IVaqueous solution according to claim 2 where the container is a bottle.6. A container for an IV aqueous solution according to claim 2 where thecontainer is a vial.
 7. A container for an IV aqueous solution accordingto claim 2 where the container is a prefilled syringe.
 8. A containerfor an IV aqueous solution according to claim 1 where thecontainer-solution contact surface is made of polyolefin or madeprimarily of polyolefin.
 9. A container for an IV aqueous solutionaccording to claim 8 where the container-solution contact surface ismade of from about 50 to about 100% polyolefin.
 10. A container for anIV aqueous solution according to claim 9 where the container-solutioncontact surface is made of from about 70 to about 90% polyolefin.
 11. Acontainer for an IV aqueous solution according to claim 10 where thecontainer-solution contact surface is made of from about 80% polyolefin.12. A container for an IV aqueous solution according to claim 1 wherethe container-solution contact surface is made of polyolefin.
 13. Acontainer for an IV aqueous solution according to claim 1 where thepolyolefin is selected from the group consisting of polyethylene,polypropylene, polybutenes, polyisoprenes and polypentenes andcopolymers and mixtures thereof.
 14. A container for an IV aqueoussolution according to claim 13 where the polyolefin is selected from thegroup consisting of polyethylene and polypropylene.
 15. A container foran IV aqueous solution according to claim 14 where the polyolefin ispolypropylene.
 16. A container for an IV aqueous solution according toclaim 1 where the a Gram-positive oxazolidinone agent is selected fromthe group consisting of linezolid and eperezolid.
 17. A container for anIV aqueous solution according to claim 16 where the Gram-positiveoxazolidinone agent is linezolid.
 18. A method of preventing loss of aGram-positive oxazolidinone agent during and following terminalsterilization with moist heat in an IV aqueous solution to be terminalsterilized with moist heat which comprises: (1) placing the IV aqueoussolution in a container to be sterilized where the container-solutioncontact surface material is made of at least 50% polyolefin and (2)moist heat sterilizing the container-solution.
 19. A method ofpreventing loss of a Gram-positive oxazolidinone agent according toclaim 18 where the container is selected from the group consisting of abag, a bottle, a vial, a large volume parenteral, a small volumeparenteral, a prefilled syringe and a cassette.
 20. A method ofpreventing loss of a Gram-positive oxazolidinone agent according toclaim 19 where the container is a bag, a bottle, a vial and a prefilledsyringe.
 21. A method of preventing loss of a Gram-positiveoxazolidinone agent according to claim 20 where the container is a bag.22. A method of preventing loss of a Gram-positive oxazolidinone agentaccording to claim 18 where the container-solution contact surface ismade of polyolefin or made primarily of polyolefin.
 23. A method ofpreventing loss of a Gram-positive oxazolidinone agent according toclaim 22 where the container-solution contact surface is made of fromabout 50 to about 100% polyolefin.
 24. A method of preventing loss of aGram-positive oxazolidinone agent according to claim 23 where thecontainer-solution contact surface is made of from about 70 to about 90%polyolefin.
 25. A method of preventing loss of a Gram-positiveoxazolidinone agent according to claim 24 where the container-solutioncontact surface is made of from about 80% polyolefin.
 26. A method ofpreventing loss of a Gram-positive oxazolidinone agent according toclaim 18 where the container-solution contact surface is made ofpolyolefin.
 27. A method of preventing loss of a Gram-positiveoxazolidinone agent according to claim 18 where the polyolefin isselected from the group consisting of polyethylene, polypropylene,polybutenes, polyisoprenes and polypentenes and copolymers and mixturesthereof.
 28. A method of preventing loss of a Gram-positiveoxazolidinone agent according to claim 27 where the polyolefin isselected from the group consisting of polyethylene and polypropylene.29. A method of preventing loss of a Gram-positive oxazolidinone agentaccording to claim 28 where the polyolefin is polypropylene.
 30. Amethod of preventing loss of a Gram-positive oxazolidinone agentaccording to claim 18 where the Gram-positive oxazolidinone agent isselected from the group consisting of linezolid and eperezolid.
 31. Amethod of preventing loss of a Gram-positive oxazolidinone agentaccording to claim 30 where the Gram-positive oxazolidinone agent islinezolid.